Reprogramming gene expression via genetic or epigenetic perturbation of transcriptional control elements has emerged as a major mechanism of oncogenesis. Using a comparative omics approach, we have defined pathogenic regulatory circuits in primary B cell tumors (follicular lymphoma, FL), linking dysfunctional enhancers to their target genes, including many involved in cellular transformation. Remarkably, a significant number of FLAREs overlap lymphoma-associated SNPs or have acquired mutations that impact enhancer function. Our epigenome-centric approach also revealed two previously unappreciated FL subtypes whose signature genes correlate with subclass-specific FLAREs. These discoveries establish distinct cistrome-based etiologies for FL and provide targets for personalized epigenetic therapies. In this regard, we have developed an innovative strategy to target pathogenic REs for reversal, using sequence-specific DNA binding proteins tethered to chromatin modifiers (termed SSCMs). Using a prototype SSCM composed of a zinc-finger (ZF) protein fused to a KRAB repressor domain, we have targeted BCL6, a key NHL oncogene, reversing its pathogenic expression and causing widespread cell death. The goal of our proposal is the development of targeted epigenetic therapeutics for NHL that can be delivered as proteins in vivo. This translational approach targets tumor-specific REs, avoiding the side effects of broad-spectrum epigenetic inhibitors. In Aim 1, FLAREs that regulate multiple cancer-associated genes will be selected by integrating bioinformatic analyses with high-throughput assays of enhancer function. These multi-genic REs, or control hubs, are attractive therapeutic targets because reversal of their aberrant function will impact the expression of several genes simultaneously, reducing the potential for tumor escape. In Aim 2, we will develop SSCMs to target these control hubs by optimizing combinations of sequence-specific domains (zinc fingers, TALEs) and chromatin modifiers (activating or repressing). In parallel, we will develop targeted nanocarrier approaches designed to improve SSCM delivery and efficacy by binding to surface markers on NHL or neovasculature in the tumor microenvironment. Aim 3 studies will utilize a mouse xenograft model of NHL to compare direct protein delivery of SSCMs with targeted nanocarrier platforms tested in Aim 2, to maximize therapeutic efficacy while minimizing immunogenicity and off-target effects in normal cells. To accomplish our goals, the applicants have assembled a team of basic, clinical and bioinformatics researchers who have been collaborating productively for several years on the foundational aspects of this problem, defining the cistrome-based etiology of NHL. Collectively, this work is expected to have an impact well beyond NHL, shepherding the use of targeted epigenetic therapies to reverse pathogenic changes in regulatory elements that mediate many cancers.